Liquid dispensing system with enhanced mixing

ABSTRACT

A dispense apparatus and system for dispensing suspensions or emulsions. The system ensures uniformity of distribution of the dispersed phase within the continuous-phase liquid by moving the fluid through the dispense cartridge, such as with a continuous or pulsating flow. In one embodiment, peristaltic pumps are positioned upstream and downstream of the dispense cartridge, in fluid communication with and forming a single loop with a fluid source. Circulation between the fluid source and the dispense cartridge is maintained. In a second embodiment, a pump circulates fluid into and out of the dispense cartridge and is also in fluid communication with a fluid source such as with a pinch valve to allow proper filling of the dispense cartridge from the fluid source. In a third embodiment, a reversing pump is placed between the dispense cartridge and fluid source to continually or continuously pump fluid into and out of the dispense cartridge.

BACKGROUND OF THE INVENTION

There are various types of dispensing apparatuses for filling parenteraland opthalmic products into vials and containers. One such type ispositive displacement fillers. These devices employ a cylinder andpiston arrangement, which contacts and dispenses the fluid. Typically,fluid enters the cylinder as the piston is in its upward motion, whichcreates a vacuum into which the fluid enters through an inlet port. Thedownward motion of the piston expels the fluid through an outlet port.The process can then be repeated. Other embodiments of positivedisplacement fillers also exist, such as those using rotary pumps.

While these fillers are popular due to their speed and accuracy, theirapplication is limited, especially in the pharmaceutical field. Thesedevices are very difficult to clean, and typically must be disassembledto be sterilized. Also, since the device actually contacts the fluid,contamination is a constant risk.

Another type of dispensing apparatus is the time/pressure filler. Thesetypically include a fluid chamber that is held under constant pressure.Fluid is dispensed through a discharge line, which is controlled by apinch type valve. The valve is opened for a precise amount of time todispense fluid. Since the pressure is held constant, and the timeinterval is constant, the amount of fluid dispensed should also beconstant. However, due to variances in the equipment and deformation ofthe discharge tube over time, these systems are less accurate thanrequired for many applications.

A third type of dispensing apparatus is the volumetric dispensingapparatus, as shown in U.S. Pat. Nos. 5,680,960, 5,480,063, andPublication No. 2005-0029301, which are hereby incorporated byreference. These devices measure and dispense a predetermined volume offluid. These systems are highly accurate and avoid problems ofcontamination common with positive displacement apparatus, since thereare no moving parts in contact with the fluid.

The above mentioned apparatus can all be used to dispense single-phasefluids but all of the apparatus described suffer from one or moresignificant drawbacks when dispensing solids dispersed in liquid(suspensions) or droplets of one liquid suspended in another liquid(emulsions). Suspension products, such as vaccines or steroid productsmay settle when not properly agitated. In the case of emulsions, the twoliquids will form droplets when they are agitated but when agitationstops, the droplets may separate into two separate layers. Either ofthese cases will result in poor content uniformity from one vial to thenext during the final dispensing of the product.

In addition, it can be difficult to clean the process equipment that hascontained suspensions or emulsions, resulting in labor intensivecleaning procedures and significant downtime to change from one batch toanother. Since the final drug product must remain sterile, rigorousaseptic processes must be adhered to in the reassembly of the dispensingapparatus.

It is therefore an object of the present invention to provide adispensing system that has provision for the mixing of suspension andemulsion products, while maintaining the integrity of the system so thatsterility is not negatively impacted. It is also an objective of thisinvention to minimize the amount of time spent cleaning the deliverysystem therefore minimizing the amount of downtime required.

SUMMARY OF THE INVENTION

The problems of the prior art have been overcome by the presentinvention, which provides a novel dispense cartridge suitable forinstallation into a host apparatus for dispensing suspensions oremulsions. The fluid dispense cartridge is particularly well suited tobe manufactured in a single-use format comprising a fluid reservoir andfill tube assembly, particularly comprising a reservoir, tubing,fittings and connectors, and a needle. The system ensures uniformitywithin the liquid by moving the fluid through the product reservoir suchas with a continuous or pulsating flow.

In one embodiment, peristaltic pumps, or other non-invasive pumpingapparatus, are positioned upstream and downstream of the fluidreservoir, in fluid communication with and forming a single loop with awell-mixed fluid source. Circulation between the fluid source and thereservoir is maintained so as to ensure a constant liquid level in thereservoir.

In a second embodiment, a peristaltic pump, or other non-invasivepumping apparatus, circulates fluid through the reservoir. A well-mixedfluid source feeds liquid to the recirculation line via a second pump orpinch valve to maintain a proper fluid level in the reservoir.

In a third embodiment, a reversing pump is placed between the reservoirand fluid source to periodically or continuously pump fluid into and outof the reservoir.

The single-use format allows for easy installation, pre-sterilization,and easy clean-up which will result in minimal downtime, significantcleaning chemical cost reduction, and greater ensured sterility. Theshape and material of the reservoir are critical in maintaining productuniformity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing one embodiment of a dispensecartridge;

FIG. 2 is a schematic diagram showing a first embodiment of the dispensesystem in accordance with the present invention;

FIG. 3 is a schematic diagram showing a second embodiment of thedispense system in accordance with the present invention;

FIG. 4 is a schematic diagram showing a third embodiment of the dispensesystem in accordance with the present invention; and

FIG. 5 is a schematic diagram showing an embodiment of the reservoir.

DETAILED DESCRIPTION OF THE INVENTION

The dispense system described here consists of a single-use dispensecartridge and a hardware component onto which the dispense cartridge canbe installed. The hardware system is described in the prior art (U.S.Pat. Nos. 5,680,960 and 5,480,063, the disclosures incorporated hereinby reference). The present invention provides for a novel dispensecartridge and method that allows for the accurate dispensing ofsuspensions or emulsions.

Preferably the fluid reservoir section of the dispense cartridge is apliable or flexible chamber or bladder, which expands and contracts tomaintain a constant internal pressure. Disposable bag-like enclosuresare particularly suitable. The tubing section of the dispense cartridgeconsists of flexible tubing such as silicone, polyethylene, or otherelastomer or polymer based tubing attached together with plasticconnectors made of materials such as polyethylene, polypropylene, orpoly-fluorocarbons.

FIG. 1 shows one embodiment of the dispense cartridge. An inlet (21) andoutlet (22) port on the reservoir (20) are connected with a tubing loop(15). A port (25) on the bottom of the reservoir (20) is provided toallow liquid to move to the tubing assembly used to deliver the productto its final containers (not shown).

FIG. 2 shows a single-loop dispensing system in accordance with oneembodiment of the present invention. The system includes a feed pump (1)in fluid communication with a well mixed, bulk fluid supply source (4)and with the inlet or fill port of a fluid reservoir of the dispensecartridge (3), and a draw pump (2) in fluid communication with an outletof reservoir of the dispense cartridge (3) and the feed to the wellmixed bulk fluid supply source (4). Configuring the feed pump (1) anddraw pump (2) in this way isolates the dispense cartridge (3) from theweight or pressure of the fluid column in the re-circulation line. Anytype of non-invasive pumping apparatus can be used, but peristalticpumps are particularly advantageous for pharmaceutical applications,because the fluid does not contact any components of the pump and sealsand valves are not necessary.

A level sensor (part of the hardware system—not shown) such as anoptical sensor or capacitance sensor can be used to monitor the fluidlevel in the reservoir of the dispense cartridge (3), and the pumpspeeds may be controlled thereby to maintain a consistent fluid level.Alternatively, a level switch can be used, in which case the pumps maybe controlled in an on/off fashion. For example, one pump may be oncontinuously but slower than the other pump, which is on intermittently.Regardless of the relative operation of the pumps, it is important thatneither pump be off for a time sufficient to allow enough of the solidsin the suspension or emulsion to separate, such that the product becomesout of specification with respect to the dispersed-phase content (i.e.,the “maximum separation time”).

FIG. 3 illustrates a second embodiment of the present invention, where acirculation-loop scheme is used to maintain flow through the dispensecartridge (3). A non-invasive pump (5), such as a peristaltic pump,circulates the product through a tubing loop (15) in fluid communicationwith an inlet and outlet of the reservoir of the dispense cartridge (3).Thus, the intake of pump (5) is in fluid communication with an outlet ofthe reservoir of the dispense cartridge (3), and the outtake of pump (5)is in fluid communication with an inlet of the reservoir of the dispensecartridge (3). The pump (5) is preferably on continuously duringoperation of the system to maintain the fluid in motion.

Tubing loop (15) is connected to a well mixed, bulk fluid supply source(4) by a relatively short length of suitable tubing (18) that passesthrough a valve (6), which may be a pinch valve. Preferably the valve(6) is controlled in response to the liquid level in the reservoir ofthe dispense cartridge (3), which may be determined with a level sensor.

This configuration requires that the pressure in the well mixed, bulkfluid supply source (4), at the transfer point, be greater than thepressure on the other side of the valve (6). This can be accomplished inany number of ways, such as by using gravity by elevating the bulk fluidsupply -source (4) or by pressurizing the bulk fluid supply source or byintroducing a Venturi restriction on the reservoir side of the valve (6)in line with the reservoir re-circulation loop. In order to avoid phaseseparation in the transfer tubing (18), the valve which when open allowsfluid communication between the bulk fluid supply source (4) and tubingloop (15), should be opened frequently. One suitable alternative totransfer valve (6) is a non-invasive pump such as a peristaltic pump.

FIG. 4 illustrates yet a further embodiment of the present invention,where an alternating or reversing pump is used to maintain flow andmixing in the reservoir. A single peristaltic pump (8), capable ofreversing direction, is in fluid communication with both the bulk fluidsupply source (4) and the reservoir of the dispense cartridge (3)through suitable tubing. The fluid level in the reservoir of thedispense cartridge (3) is monitored, such as with a level switch. Whenthe fluid level in the reservoir reaches a predetermined level, the pump(8) remains on but alternates direction so that product is alternatelypumped into and out of the reservoir on a periodic or continuous basis.If the level in the reservoir of the dispense cartridge (3) falls belowthe predetermined level, the pump (8) is placed in a single directionmode to fill the reservoir to the desired level, and is then againplaced in the alternating mode to alternately pump product into and outof the reservoir to maintain flow and prevent the solids from settling.

In the event the withdrawal of fluid from the reservoir of the dispensecartridge (3) does not mix the reservoir contents as efficiently as thefilling of the reservoir, the speed of the pump (8) may also alternatein accord with the pump direction so that the time that the pump iswithdrawing fluid is less than 50% of the pump cycle time or the cycletime may be minimized.

FIG. 5 shows a preferred embodiment of the reservoir (20) section of thedispense cartridge. The preferred embodiment is designed to maximize thefluid motion in the reservoir (20) and minimize any potential stagnationzones. This embodiment shows the inlet (21) and outlet (22) ports of thereservoir (20) located on opposite sides of the reservoir (20). A port(25) on the bottom of the reservoir (20) allows fluid to move to thetubing assembly used to deliver the product to its final containers (notshown).

Those skilled in the art will appreciate that although the abovedescription details the use of tubing, other types of fluid lines areacceptable, including suitable ducting, piping, etc. In addition, thoseskilled in the art will appreciate the multitude of configurationsavailable for the dispense cartridge reservoir and the multitude ofconfigurations available for the circulation loop.

1. A fluid dispensing apparatus for dispensing a predetermined volume offluid, comprising a reservoir having a dispense port, a first pump influid communication with a fluid source comprising a two-phase fluid andsaid reservoir for pumping said two-phase fluid into said reservoir, asecond pump in fluid communication with said reservoir and said fluidsource for pumping said two-phase fluid from said reservoir, and a fluidlevel determining device for determining the fluid level in saidreservoir, wherein in response to said determined fluid level, saidfirst and second pumps maintain circulation between said fluid sourceand said reservoir such that a constant liquid level in said reservoiris ensured, and such that said two-phase fluid remains homogenous. 2.The fluid dispensing system of claim 1, wherein said first and secondpumps are peristaltic pumps.
 3. The fluid dispensing system of claim 1,wherein said fluid is a suspension.
 4. The fluid dispensing system ofclaim 1, wherein said fluid is an emulsion.
 5. The fluid dispensingsystem of claim 1, further comprising a controller responsive to saidfluid level determining device for controlling the speed of said firstand second pumps based upon the fluid level in said reservoir.
 6. Thefluid dispensing system of claim 1, further comprising a dispensecartridge which houses said reservoir.
 7. A method of minimizing in areservoir the separation of a two-phase fluid, comprising providing asupply source of said fluid in fluid communication with said reservoir,determining the level of said fluid in said reservoir, pumping saidfluid from said source to said reservoir with a first pump, and pumpingsaid fluid from said reservoir to said source with a second pump,wherein in response to said determined fluid level, said first andsecond pumps maintain circulation between said supply of fluid and saidreservoir such that a constant liquid level in said reservoir isensured, and such that said two-phase fluid remains homogenous forultimate dispensing from said reservoir to a point of use.
 8. The methodof claim 7, wherein said fluid is a suspension.
 9. The method of claim7, wherein said fluid is an emulsion.